Evolution of subcutaneous adipose tissue fibrosis after bariatric surgery.

AIM: Obesity is associated with the development of metabolic complications such as insulin resistance (IR). The mechanisms leading to IR remain unclear. This study aimed to investigate the relationship between adipose tissue fibrosis and IR in obese patients before and after bariatric surgery. METHODS: Thirty-five obese patients awaiting bariatric surgery (12 with type 2 diabetes) were included in the study. Non-diabetic patients were classified as either insulin-sensitive (n=11) or insulin-resistant (n=12), based on the Matsuda insulin sensitivity index (ISIMatsuda). Homoeostasis model assessment (HOMA-IR) was used for longitudinal evaluation of insulin resistance. Fibrosis was quantified by Masson's trichrome staining on microscopy, and mRNA levels of fibrosis-related genes were examined in subcutaneous (SAT) and visceral adipose tissue (VAT) biopsies collected during and 6 months after bariatric surgery (SAT only). RESULTS: Despite their similar age, body mass index and fat mass, SAT fibrosis was significantly higher in diabetic vs insulin-sensitive patients (P<0.05), and associated with IR as assessed by both ISIMatsuda (r=-0.417, P=0.038) and HOMA-IR (r=0.464, P=0.007) at baseline, whereas VAT fibrosis was not. Six months after surgery and significant weight loss, fibrosis levels remained unchanged in SAT, although IR was significantly reduced in all groups (P<0.0001). No correlation was found between SAT fibrosis and IR after surgery. CONCLUSION: Overall, these results show a significant but, most likely, transient association between SAT fibrosis and IR in obese humans.

Could T cells be involved in lung deterioration and hyperglycemia in cystic fibrosis?

Cystic fibrosis-related diabetes (CFRD) is the most frequent complication of cystic fibrosis (CF) and associated with increased mortality. Why patients have an accelerated loss of lung function before the diagnosis of CFRD remains poorly understood. We reported that patients with or without CFRD had increased glucose excursions when compared to healthy peers. Studies have demonstrated that patients with CF have increased glucose fluctuations and hyperglycemia and that this may affect the clinical course of CF and lead to lymphocyte dysfunction. T-helper 17 (Th17) lymphocytes produce and secrete the pro-inflammatory cytokine IL-17. The Th17 pathway is involved in CF lung inflammation, ß-cell destruction in type 1 diabetes (T1D) and Th17 cells of patients with type 2 diabetes have increased production of IL-17 when compared to healthy peers. Also, regulatory T-cells (Tregs) have been shown to be dysfunctional and produce IL-17 in T1D. Furthermore, vitamin D can affect inflammation in CF, diabetes and the differentiation of lymphocytes. In this review, we discuss the potential roles of hyperglycemia on Th17 cells, Tregs and IL-17 as a potential cause for accelerated lung function decline before CFRD and how this could be modulated by vitamin D or by directly intervening in the IL-17A pathway.

Regulation of fat metabolism in the liver: link to non-alcoholic hepatic steatosis and impact of physical exercise.

Hepatic steatosis may develop as a consequence of several dysfunctions. An increased circulating non-esterified fatty acid (NEFA) pool seems to be a major determinant in the pathogenesis of non-alcoholic fatty liver disease. Increased activation of the transcription factor sterol-regulatory-element-binding protein-1c, which promotes fatty acid synthesis, also contributes to hepatic fat accumulation. Increased hepatic fat oxidation with hepatic steatosis may be triggered by increased hepatic fat concentrations through the action of hepatic peroxisomes mediated by peroxisome proliferator-activated receptor alpha. Finally, inhibition in very low density lipoprotein secretion may also result in hepatic steatosis. This appears to be mainly controlled by the esterification of NEFAs into triacylglycerols by diacyglycerol acyltransferase-1 and -2 and the microsomal transfer protein. Physical exercise would interfere with the development of hepatic steatosis by stimulating lipid oxidation and inhibiting lipid synthesis in liver through the activation of the AMP-activated protein kinase pathway.

Evidence of hepatic glucagon resistance associated with hepatic steatosis: reversal effect of training.

The present study was undertaken to test the hypothesis that a high-fat diet-induced hepatic steatosis is associated with a reduction in hepatic glucose output (HGO) in response to a hyperglucagonemic infusion, and that this postulated state of hepatic glucagon resistance in high-fat fed rats is attenuated by concurrent exercise training. In four groups of anesthetized rats, glucagon (2 ug/kg/min iv) was infused over a period of 60 min to measure HGO. Two groups of rats were either fed a standard (SD) or a high-fat (HF; 42 % kcal) diet for eight weeks and were assigned either to a Sedentary (Sed) or a treadmill-trained (TR) group. Training was initiated two weeks after the beginning of the diet protocol and was progressively increased over a period of 6 weeks reaching 60 min at 26 m/min, 10 % grade, for the last 3 weeks. The HF compared to the SD diet resulted in approximately 28 % higher (p < 0.01) liver triglyceride levels in Sed rats. This increase was completely prevented by the exercise training program in the HF-TR group. Plasma glucagon ( approximately 90,000 pg/ml) and insulin ( approximately 500 pmol/l) levels were increased to a similar extent in all four groups, with the exception of higher (p<0.05) insulin levels in SD-Sed group. Glucagon induced-hyperglycemia ( approximately 300 mg/dl) was higher (p<0.05) in the SD-Sed than in HF-Sed and SD-TR groups. Glucagon infusion resulted in a significantly (p<0.05) lower increase ( approximately 35 %) in HGO in HF-Sed compared to SD-Sed group. The lower level of HGO in HF-Sed compared to SD-Sed rats was observed whether HGO was measured after 25, 40, or 60 min of glucagon infusion. Exercise training in HF fed rats resulted in a significant (p<0.05) attenuation (50 %) of the state of HF-induced glucagon resistance. Comparisons of all individual liver triglyceride and 60-min HGO values revealed that liver triglyceride values were highly (p<0.001) predictive of the decreased glucagon action on HGO (R= -0.849). The present results indicate that the feeding of a high-fat diet induces a state of hepatic glucagon resistance, which is partially attenuated by concurrent exercise training. It is suggested that liver lipid infiltration may interfere with the action of glucagon, thus inducing glucagon resistance in liver.

Effects of introducing physical training in the course of a 16-week high-fat diet regimen on hepatic steatosis, adipose tissue fat accumulation, and plasma lipid profile.

OBJECTIVE: We recently reported that an 8-week high-fat diet-induced hepatic steatosis was completely prevented if an exercise training programme was introduced and pursued concurrently with the diet. The purpose of the present study was to determine the extent to which introducing exercise training at mid-point in the course of a 16-week high-fat diet regimen contributes to the reversal of liver lipid infiltration and the reduction of blood lipid profile deterioration and body fat accumulation. DESIGN AND SUBJECTS: Two groups of rats were fed a high-fat diet (42% kcal) for 16 weeks, one remaining sedentary during this entire period (HF-Sed) and the other being exercise trained for the last 8 weeks (HF-Tr). A third group was fed a standard diet and remained sedentary for all 16 weeks (SD-Sed). Training (5 days/week for 8 weeks) began 8 weeks after introducing the high-fat diet and consisted of treadmill running that was progressively increased to reach 60 min at 26 m/min, 10% grade, for the last 4 weeks. MEASUREMENTS: Various parameters including liver lipid infiltration, fat depots and blood lipids. RESULTS: Unexpectedly, liver lipid infiltration was not significantly higher in HF-Sed than in SD-Sed rats (means+/-s.e.: 14.9+/-1.7 vs 12.3+/-0.4 mg/g; P>0.05). High-fat compared to age-matched standard fed rats also showed an absence of difference (P>0.05) in the weight of total visceral fat pads (13%), plasma nonesterified fatty acids (NEFA), and leptin concentrations, but depicted significantly (P<0.01) higher values for subcutaneous fat pad weight and plasma triacyglycerol. Exercise training largely decreased visceral and subcutaneous fat accumulation by 30 and 26%, respectively (P<0.01) as well as NEFA, triacylglycerol, and leptin concentrations (P<0.01). CONCLUSION: Liver lipid infiltration does not seem to progress linearly over 16 weeks of high-fat feeding in light of what has previously been observed after 8 weeks of high-fat feeding. Introducing a training programme in the course of a 16-week high-fat diet protocol reduced adiposity, plasma NEFA, and leptin concentrations below the levels observed in standard fed rats. These data indicate that, exercise training, whether conducted concurrently or introduced during the course of a high-fat diet, is an asset to reduce the deleterious effects of a high-fat diet.

Specific mucosal erosions in hypereosinophilic syndrome. Evidence for eosinophil protein deposition.

BACKGROUND: Mucosal erosions can be a presenting feature of the hypereosinophilic syndrome. The aim of this study was to analyze in situ the presence of eosinophil proteins and the state of eosinophil activation. Biopsy specimens of mucosal lesions and normal skin were taken from two men with oral and genital erosions typical of hypereosinophilic syndrome. Tissue sections were immunohistochemically labeled with anti-major basic protein, anti-eosinophil-derived neurotoxin, and anti-eosinophil peroxidase antibodies. The same specimens were also subjected to electron microscope examination. OBSERVATIONS: Eroded specimens displayed areas of eosinophil spongiosis within which extracellular deposits of eosinophil peroxidase, major basic protein, and eosinophil-derived neurotoxin were present. In normal skin, only a few eosinophils were present within the capillary lumen, and no extracellular deposits of these proteins were seen. Under the electron microscope, the cytoplasmic membranes of eosinophils located around the erosion were disrupted. Remnants of necrotic keratinocytes were found near these lysed eosinophils. CONCLUSION: As with other involved organs in hypereosinophilic syndrome, mucosal erosions seem to be the consequence of eosinophil protein release.